A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain

Chen, Wenling; Marvizón, Juan Carlos G.

doi:10.1101/2020.02.18.954859

Cited by 3 publications

(10 citation statements)

References 51 publications

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“…Finally, MOR inhibits voltage-gated Ca 2+ channels in dorsal root ganglia neurons of CFA sensitized mice in a ligandindependent manner since it is disrupted with naltrexone but not 6β-naltrexol (Walwyn et al, 2016). Naltrexone-induced hyperalgesia after recovery from CFA administration was reproduced several times in different labs (Chen & Marvizón, 2020a, 2020bCorder et al, 2013;Feehan & Zadina, 2019;Severino et al, 2018;Taylor et al, 2019;Walwyn et al, 2016) and then extended to chronic morphine (Roeckel et al, 2017) and postoperative (Feehan & Zadina, 2019) pain models. Naltrexone also induces signs of spontaneous and affective pain as assessed by the grimace scale score and conditioned place preference paradigm (Corder et al, 2013).…”

Section: Mu Opioid Receptor (Mor)mentioning

confidence: 99%

“…Recently, latent pain sensitization was identified in other well-established models of persistent pain, as paw plantar incision (Campillo et al, 2011;Romero-Alejo et al, 2016b), nerve injury (Chen & Marvizón, 2020a, 2020bFu et al, 2020;Solway et al, 2011), carrageenan-(Le Roy et al, 2011 or Complete Freund's Adjuvant (CFA)-induced inflammatory pain (Araldi et al, 2017;Chen et al, 2018b;Chen & Marvizón, 2020a, 2020bCorder et al, 2013;Feehan & Zadina, 2019;Marvizón et al, 2015;Severino et al, 2018;Solway et al, 2011;Taylor et al, 2019;Walwyn et al, 2016) and Nerve Growth Factor (NGF) induced non-specific low back pain (Zhang et al, 2017). Thus, nociceptive inputs can also indirectly stimulate endogenous opioid system to initiate sustained latent sensitization to pain.…”

Section: Animal Models Of Latent Pain Sensitizationmentioning

confidence: 99%

“…NMDA receptor, adenylate cyclase and protein kinase A, three key elements that contributes to latent pain sensitization (Célèrier et al, 2001;Corder et al, 2013;Fu et al, 2019) are also known to mediate substance P release by primary afferent fibers in the spinal cord dorsal horn (Chen et al, 2018a;Marvizón et al, 1997). Besides, presynaptic MOR inhibits substance P release (Chen et al, 2018a) and is responsible for endogenous analgesia in latent pain sensitization (Chen & Marvizón, 2020a, 2020bCorder et al, 2013;Feehan & Zadina, 2019;Roeckel et al, 2017;Severino et al, 2018;Walwyn et al, 2016). Indeed, loss of MOR in central terminal of primary afferents in Nav1.8cre/flMOR mice abolished both MOR inhibition of NMDA receptor induced substance P release and latent pain sensitization (Severino et al, 2018).…”

Section: Neurokinin 1 Receptor (Nk1r)mentioning

confidence: 99%

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Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization

Gerum¹,

Simonin²

2022

Pharmacology & Therapeutics

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Chronic pain is a debilitating disorder that can occur as painful episodes that alternates with bouts of remission and occurs despite healing of the primary insult. Those episodes are often triggered by stressful events. In the last decades, a similar situation has been evidenced in a wide variety of rodent models (including inflammatory pain, neuropathy and opioid-induced hyperalgesia) where animals develop a chronic latent hyperalgesia that silently persists after behavioral signs of pain resolution. This state, referred as latent pain sensitization, is due to the compensatory activation of antinociceptive systems, such as the opioid system or NPY and its receptors. A transitory phase of hyperalgesia can then be reinstated by pharmacological or genetic blockade of these antinociceptive systems or by submitting animals to acute stress. Those observations reveal that there is a constant endogenous analgesia responsible for chronic pain inhibition that might paradoxically contribute to maintain this maladaptive state and could then participate to the transition from acute to chronic pain. Thus, demonstration of the existence of this phenomenon in humans and a better understanding of the mechanisms by which latent pain sensitization develops and maintains over long periods of time will be of particular interest to help identifying new therapeutic strategies and targets for chronic pain treatment. The present review aims to recapitulate behavioral expression, potential clinical relevance, cellular mechanisms and intracellular signaling pathways involved so far in latent pain sensitization.

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Section: Mu Opioid Receptor (Mor)mentioning

confidence: 99%

Section: Animal Models Of Latent Pain Sensitizationmentioning

confidence: 99%

Section: Neurokinin 1 Receptor (Nk1r)mentioning

confidence: 99%

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Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization

Gerum¹,

Simonin²

2022

Pharmacology & Therapeutics

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“…The reduce the number of animals used, the CFA and SNI control groups were shared with another study on the effect of the Src family kinase inhibitor PP2 on latent sensitization (Chen and Marvizón, 2020). The target sample size was n = 7-8 rats per group based on a power analysis.…”

Section: Sample Size Randomization and Blindingmentioning

confidence: 99%

“…Still, our findings provide a strong indication that NK1Rs are involved in the maintenance of latent sensitization. In a parallel study, we used the same criterion to show that a Src family kinase also maintains latent sensitization (Chen and Marvizón, 2020).…”

Section: Nk1rs Mediate the Maintenance Of Latent Sensitizationmentioning

confidence: 99%

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain

Chen

Marvizón

2020

Preprint

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Latent sensitization is a model of chronic pain in which a persistent state of pain hypersensitivity is suppressed by opioid receptors, as evidenced by the ability of opioid antagonists to induce a period of mechanical allodynia. Our objective was to determine if substance P and its neurokinin 1 receptor (NK1R) mediate the maintenance of latent sensitization. Latent sensitization was induced by injecting rats in the hindpaw with complete Freund's adjuvant (CFA), or by spared nerve injury (SNI). When responses to von Frey filaments returned to baseline (day 28), the rats were injected intrathecally with saline or the NK1R antagonist RP67580, followed 15 min later by intrathecal naltrexone. In both pain models, the saline-injected rats developed allodynia for 2 h after naltrexone, but not the RP67580injected rats. Saline or RP67580 were injected daily for two more days. Five days later (day 35), naltrexone was injected intrathecally. Again, the saline-injected rats, but not the RP67580injected rats, developed allodynia in response to naltrexone. To determine if there is sustained activation of NK1Rs during latent sensitization, NK1R internalization was measured in lamina I neurons in rats injected in the paw with saline or CFA, and then injected intrathecally with saline or naltrexone on day 28. The rats injected with CFA had a small amount of NK1R internalization that was significantly higher than in the saline-injected rats. Naltrexone increased NK1R internalization in the CFA-injected rats but nor in the saline-injected rats. Therefore, sustained activation of NK1Rs maintains pain hypersensitivity during latent sensitization.

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Morphine-induced mechanical hypersensitivity in mice requires δ receptors, β-arrestin2 and c-Src activity

Singleton

Hales

2022

Preprint

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Background: Morphine diminishes acute pain, but long-term use is compromised by tolerance and hyperalgesia. Studies implicate delta receptors, beta-arrestin2 and Src kinase in tolerance. We examined whether these proteins are also involved in morphine-induced hypersensitivity (MIH). A common pathway for tolerance and hypersensitivity may provide a single target to guide improved analgesic approaches. Methods: We examined mechanical sensitivity using automated von Frey in wild type (WT) and transgenic male and female C57Bl/6 mice before and after hind paw inflammation by complete Freund's adjuvant (CFA). We explored the expression of opioid genes in the spinal cord using quantitative RT-PCR. Results: CFA-evoked hypersensitivity ceased on day 7 in WT mice but persisted in mu -/- mice. Recovery was delayed until day 13 in delta-/- mice. Restoration to basal sensitivity in WT mice occurred with increased delta expression. By contrast, kappa expression was reduced, while mu remained unchanged. Daily morphine reduced hypersensitivity in WT mice on day 3 compared to controls, however hypersensitivity recurred on day 9 and beyond. By contrast, WT mice had no recurrence of hypersensitivity in the absence of daily morphine. We used beta-arrestin2-/-, delta-/- and Src inhibition by dasatinib in WT mice to establish whether these approaches, which diminish tolerance, also attenuate MIH. While none of these approaches affected CFA-evoked inflammation or acute hypersensitivity, all caused sustained morphine anti-hypersensitivity, abolishing MIH. Conclusions: Like morphine tolerance, MIH in this model requires delta receptors, beta-arrestin2 and Src activity. Our findings suggest that MIH is caused by a tolerance-induced reduction in endogenous opioid signalling.

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A Src family kinase maintains latent sensitization in rats, a model of inflammatory and neuropathic pain

Cited by 3 publications

References 51 publications

Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization

Behavioral characterization, potential clinical relevance and mechanisms of latent pain sensitization

Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain

Morphine-induced mechanical hypersensitivity in mice requires δ receptors, β-arrestin2 and c-Src activity

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